Genomic mapping of direct and correlated responses to long-term selection for rapid growth rate in mice

Abstract

Understanding the genetic architecture of traits such as growth, body composition, and energy balance has become a primary focus for biomedical and agricultural research. The objective of this study was to map QTL in a large F(2) (n = 1181) population resulting from an intercross between the M16 and ICR lines of mice. The M16 line, developed by long-term selection for 3- to 6-week weight gain, is larger, heavier, fatter, hyperphagic, and diabetic relative to its randomly selected control line of ICR origin. The F(2) population was phenotyped for growth and energy intake at weekly intervals from 4 to 8 weeks of age and for body composition and plasma levels of insulin, leptin, TNFalpha, IL6, and glucose at 8 weeks and was genotyped for 80 microsatellite markers. Since the F(2) was a cross between a selection line and its unselected control, the QTL identified likely represent genes that contributed to direct and correlated responses to long-term selection for rapid growth rate. Across all traits measured, 95 QTL were identified, likely representing 19 unique regions on 13 chromosomes. Four chromosomes (2, 6, 11, and 17) harbored loci contributing disproportionately to selection response. Several QTL demonstrating differential regulation of regional adipose deposition and age-dependent regulation of growth and energy consumption were identified.

Figure 1.—

Genomic mapping of direct and correlated responses to long-term selection for 3- to 6-week weight gain in mice, representing 66 QTL identified in the M16 × ICR F₂ cross. QTL not included in this figure were for fat traits expressed in grams, TTM, GAIN4–8, and weekly FIA. Colored lines represent confidence intervals for QTL according to trait. Gray dots on the colored lines show estimated positions of QTL peaks.

Figure 2.—

Chromosome maps for (A) MMU7 showing significant QTL for epididymal/perimetrial fat with lack of QTL for other fat traits and (B) MMU4 showing significant QTL for subcutaneous fat with lack of QTL for other fat traits. The x-axis represents the length of the chromosome in centimorgans. The y-axis is the LOD score with a 5% genome-wide threshold set at 3.3. Trait definitions can be found in Table 4.

Figure 3.—

Chromosome map of MMU9 showing age-specific regulation of feed intake. The x-axis represents the length of the chromosome in centimorgans. The y-axis is the LOD score with a 5% genome-wide threshold set at 3.3. Trait definitions can be found in Table 5.

Figure 4.—

Chromosome maps for (A) MMU11 showing QTL curves for feed intake, percentage overall body fat, percentage gonadal/perimetrial adipose pad, percentage subcutaneous adipose pad, 3- to 6-week gain, and 8-week body weight and (B) MMU2 showing regions regulating fat and growth traits. The x-axis represents the length of the chromosome in centimorgans. The y-axis is the LOD score with a 5% genome-wide threshold set at 3.3. Trait definitions can be found in Tables 3–5.

Figure 5.—

Chromosome map of MMU17 showing two separate regions regulating fat and growth traits. The x-axis represents the length of the chromosome in centimorgans. The y-axis is the LOD score with a 5% genome-wide threshold set at 3.3. Trait definitions are in Tables 4 and 5.